Investigational New Drugs

, Volume 33, Issue 5, pp 1100–1107 | Cite as

A phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors

  • Suzanne F. JonesEmail author
  • Lillian L. Siu
  • Johanna C. Bendell
  • James M. Cleary
  • Albiruni R. A. Razak
  • Jeffrey R. Infante
  • Shuchi S. Pandya
  • Philippe L. Bedard
  • Kristen J. Pierce
  • Brett Houk
  • W. Gregory Roberts
  • S. Martin Shreeve
  • Geoffrey I. Shapiro


Objective VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk2). This phase I dose-escalation study was conducted in patients with advanced solid malignancies. Methods Using a traditional 3 + 3 design, VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three to six patients. In cycle 1, a lead-in dose was administered to assess single-dose pharmacokinetics; steady-state pharmacokinetics was assessed after 15 days of continuous dosing. Dose escalation was performed in the fasted state, and repeated in two additional cohorts in the fed state. Results Forty-six patients were treated across nine dose levels (12.5–750 mg b.i.d.). Dose-limiting toxicities, comprising headache (n = 1), fatigue (n = 1) and unconjugated hyperbilirubinemia (n = 3), occurred at the 300- or 425-mg b.i.d. dose level and were reversible. Frequent adverse events included nausea (37 %), fatigue (33 %), vomiting (28 %), diarrhea (22 %) and headache (22 %). A maximum-tolerated dose was not defined. Dose escalation was stopped at the 750-mg b.i.d. dose due to decreased serum exposure in the 500- and 750-mg versus 300- and 425-mg groups. Food delayed the time to peak serum concentration without affecting serum drug exposure. No radiographic responses were reported. Disease stabilization at ~12 weeks occurred in six of 37 (16 %) patients receiving doses ≥100 mg b.i.d. Conclusions VS-6063 has an acceptable safety profile. Treatment-related adverse events were mild to moderate, and reversible. The recommended phase II fasting dose of VS-6063 is 425 mg b.i.d.


Focal adhesion kinase Proline-rich tyrosine kinase-2 Dose-escalation study VS-6063 Defactinib 



This study was sponsored by Pfizer Inc. Medical writing support was provided by Andrew Fitton, PhD, of Engage Scientific Solutions, and was funded by Pfizer Inc.

Source of funding

Drs. K. Pierce, B. Houk, and W.G. Roberts are full-time employees of Pfizer Inc. At the time the study was conducted, Dr. S.M. Shreeve was an employee of Pfizer Inc.; currently he is an employee of Janssen Pharmaceutical Companies of Johnson and Johnson. At the time the study was conducted, Dr. S. Pandya was an employee of Beth Israel Deaconess Medical Center; currently she is an employee of Acceleron Pharma. Dr. L. Siu receives research funding for clinical trial support from Pfizer Inc.

Conflict of interest

Dr. G. Shapiro, Dr P. Bedard, Dr J. Infante, Dr A Razak, Dr S. Jones, and Dr J. Cleary have no financial conflicts of interest to declare.


  1. 1.
    Schwock J, Dhani N, Hedley DW (2010) Targeting focal adhesion kinase signaling in tumor growth and metastasis. Expert Opin Ther Targets 14:77–94. doi: 10.1517/14728220903460340 CrossRefPubMedGoogle Scholar
  2. 2.
    Schultze A, Fiedler W (2010) Therapeutic potential and limitations of new FAK inhibitors in the treatment of cancer. Expert Opin Investig Drugs 19:777–788. doi: 10.1517/13543784.2010.489548 CrossRefPubMedGoogle Scholar
  3. 3.
    Schlaepfer DD, Mitra SK, Ilic D (2004) Control of motile and invasive cell phenotypes by focal adhesion kinase. Biochim Biophys Acta 1692:77–102. doi: 10.1016/j.bbamcr.2004.04.008 CrossRefPubMedGoogle Scholar
  4. 4.
    Hao H, Naomoto Y, Bao X et al (2009) Focal adhesion kinase as potential target for cancer therapy (Review). Oncol Rep 22:973–979CrossRefPubMedGoogle Scholar
  5. 5.
    Tilghman RW, Parsons JT (2008) Focal adhesion kinase as a regulator of cell tension in the progression of cancer. Semin Cancer Biol 18:45–52. doi: 10.1016/j.semcancer.2007.08.002 PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Sieg DJ, Hauck CR, Ilic D, Klingbeil CK, Schaefer E, Damsky CH, Schlaepfer DD (2000) FAK integrates growth-factor and integrin signals to promote cell migration. Nat Cell Biol 2:249–256. doi: 10.1038/35010517 CrossRefPubMedGoogle Scholar
  7. 7.
    Zhao X, Guan JL (2011) Focal adhesion kinase and its signaling pathways in cell migration and angiogenesis. Adv Drug Deliv Rev 63:610–615. doi: 10.1016/j.addr.2010.11.001 PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Schlaepfer DD, Mitra SK (2004) Multiple connections link FAK to cell motility and invasion. Curr Opin Genet Dev 14:92–101. doi: 10.1016/j.gde.2003.12.002 CrossRefPubMedGoogle Scholar
  9. 9.
    Siesser PM, Hanks SK (2006) The signaling and biological implications of FAK overexpression in cancer. Clin Cancer Res 12:3233–3237. doi: 10.1158/1078-0432.CCR-06-0456 CrossRefPubMedGoogle Scholar
  10. 10.
    Golubovskaya VM (2010) Focal adhesion kinase as a cancer therapy target. Anti Cancer Agents Med Chem 10:735–741CrossRefGoogle Scholar
  11. 11.
    Smith CS, Golubovskaya VM, Peck E, Xu LH, Monia BP, Yang X, Cance WG (2005) Effect of focal adhesion kinase (FAK) downregulation with FAK antisense oligonucleotides and 5-fluorouracil on the viability of melanoma cell lines. Melanoma Res 15:357–362CrossRefPubMedGoogle Scholar
  12. 12.
    Wu ZM, Yuan XH, Jiang PC, Li ZQ, Wu T (2006) Antisense oligonucleodes targeting the focal adhesion kinase inhibit proliferation, induce apoptosis and cooperate with cytotoxic drugs in human glioma cells. J Neurooncol 77:117–123. doi: 10.1007/s11060-005-9025-9 CrossRefPubMedGoogle Scholar
  13. 13.
    Shen TL, Park AY, Alcaraz A, Peng X, Jang I, Koni P, Flavell RA, Gu H, Guan JL (2005) Conditional knockout of focal adhesion kinase in endothelial cells reveals its role in angiogenesis and vascular development in late embryogenesis. J Cell Biol 169:941–952. doi: 10.1083/jcb.200411155 PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Golubovskaya VM, Huang G, Ho B, Yemma M, Morrison CD, Lee J, Eliceiri BP, Cance WG (2013) Pharmacologic blockade of FAK autophosphorylation decreases human glioblastoma tumor growth and synergizes with temozolomide. Mol Cancer Ther 12:162–172. doi: 10.1158/1535-7163.MCT-12-0701 PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Provenzano PP, Keely PJ (2009) The role of focal adhesion kinase in tumor initiation and progression. Cell Adhes Migr 3:347–350CrossRefGoogle Scholar
  16. 16.
    Parsons JT, Slack-Davis J, Tilghman R, Roberts WG (2008) Focal adhesion kinase: targeting adhesion signaling pathways for therapeutic intervention. Clin Cancer Res 14:627–632. doi: 10.1158/1078-0432.CCR-07-2220 CrossRefPubMedGoogle Scholar
  17. 17.
    Roberts WG, Ung E, Whalen P et al (2008) Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271. Cancer Res 68:1935–1944. doi: 10.1158/0008-5472.CAN-07-5155 CrossRefPubMedGoogle Scholar
  18. 18.
    Lipinski CA, Loftus JC (2010) Targeting Pyk2 for therapeutic intervention. Expert Opin Ther Targets 14:95–108. doi: 10.1517/14728220903473194 PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Hall JE, Fu W, Schaller MD (2011) Focal adhesion kinase: exploring Fak structure to gain insight into function. Int Rev Cell Mol Biol 288:185–225. doi: 10.1016/B978-0-12-386041-5.00005-4 CrossRefPubMedGoogle Scholar
  20. 20.
    Buckbinder L, Crawford DT, Qi H et al (2007) Proline-rich tyrosine kinase 2 regulates osteoprogenitor cells and bone formation, and offers an anabolic treatment approach for osteoporosis. Proc Natl Acad Sci U S A 104:10619–10624. doi: 10.1073/pnas.0701421104 PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Schaller MD (2010) Cellular functions of FAK kinases: insight into molecular mechanisms and novel functions. J Cell Sci 123:1007–1013. doi: 10.1242/jcs.045112 CrossRefPubMedGoogle Scholar
  22. 22.
    Weis SM, Lim ST, Lutu-Fuga KM et al (2008) Compensatory role for Pyk2 during angiogenesis in adult mice lacking endothelial cell FAK. J Cell Biol 181:43–50. doi: 10.1083/jcb.200710038 PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Fan H, Guan JL (2011) Compensatory function of Pyk2 protein in the promotion of focal adhesion kinase (FAK)-null mammary cancer stem cell tumorigenicity and metastatic activity. J Biol Chem 286:18573–18582. doi: 10.1074/jbc.M110.200717 PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Infante JR, Camidge DR, Mileshkin LR et al (2012) Safety, pharmacokinetic, and pharmacodynamic phase I dose-escalation trial of PF-00562271, an inhibitor of focal adhesion kinase, in advanced solid tumors. J Clin Oncol 30:1527–1533. doi: 10.1200/JCO.2011.38.9346 CrossRefPubMedGoogle Scholar
  25. 25.
    Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216CrossRefPubMedGoogle Scholar
  26. 26.
    Jemnitz K, Lengyel G, Vereczkey L (2002) In vitro induction of bilirubin conjugation in primary rat hepatocyte culture. Biochem Biophys Res Commun 291:29–33. doi: 10.1006/bbrc.2002.6400 CrossRefPubMedGoogle Scholar
  27. 27.
    Zucker SD, Qin X, Rouster SD, Yu F, Green RM, Keshavan P, Feinberg J, Sherman KE (2001) Mechanism of indinavir-induced hyperbilirubinemia. Proc Natl Acad Sci U S A 98:12671–12676. doi: 10.1073/pnas.231140698 PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Zhang D, Chando TJ, Everett DW, Patten CJ, Dehal SS, Humphreys WG (2005) In vitro inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation. Drug Metab Dispos 33:1729–1739. doi: 10.1124/dmd.105.005447 CrossRefPubMedGoogle Scholar
  29. 29.
    Soria JC, Gan HK, Arkenau HT (2012) Phase I clinical and pharmacologic study of the focal adhesion kinase (FAK) inhibitor GSK2256098 in pts with advanced solid tumors. J Clin Oncol 30(Suppl):Abst. 3000Google Scholar
  30. 30.
    Konstantinidou G, Ramadori G, Torti F et al (2013) RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas. Cancer Discov 3:444–457. doi: 10.1158/2159-8290.CD-12-0388 PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Poulikakos PI, Xiao GH, Gallagher R, Jablonski S, Jhanwar SC, Testa JR (2006) Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK. Oncogene 25:5960–5968. doi: 10.1038/sj.onc.1209587 CrossRefPubMedGoogle Scholar
  32. 32.
    Thurneysen C, Opitz I, Kurtz S, Weder W, Stahel RA, Felley-Bosco E (2009) Functional inactivation of NF2/merlin in human mesothelioma. Lung Cancer 64:140–147. doi: 10.1016/j.lungcan.2008.08.014 CrossRefPubMedGoogle Scholar
  33. 33.
    Shapiro IM, Kolev VN, Vidal CM et al (2014) Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship. Sci Transl Med 6:237–268. doi: 10.1126/scitranslmed.3008639 Google Scholar
  34. 34.
    Soria JC, Plummer R, Ranson M, Gan H, Arkenau HT, Zalcman G, Blagden S (2012) Loss of the tumor suppressor Merlin as a potential predictive biomarker of clinical activity for the oral, focal adhesion kinase (FAK) inhibitor GSK2256098 in pts with recurrent mesothelioma. Eur J Cancer 48(Suppl 6):188, Abst. 610 CrossRefGoogle Scholar
  35. 35.
    Xu Q, Kolev VN, Vidal CM, Shapiro IM, Ring JE, Padval MV, Keegan M, Pachter JA (2012) FAK inhibitor VS-4718 attenuates breast cancer stem cell function and inhibitors tumor growth in vivo. Eur J Cancer 48(Suppl 6):122, Abst. 400 CrossRefGoogle Scholar
  36. 36.
    Sood AK, Coffin JE, Schneider GB, Fletcher MS, DeYoung BR, Gruman LM, Gershenson DM, Schaller MD, Hendrix MJ (2004) Biological significance of focal adhesion kinase in ovarian cancer: role in migration and invasion. Am J Pathol 165:1087–1095. doi: 10.1016/S0002-9440(10)63370-6 PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    Patel MR, Infante JR, Moore KN, Keegan M, Poli A, Padval M, Jones SF, Horobin J, Burris HA (2014) Phase 1/1b study of the FAK inhibitor defactinib (VS-6063) in combination with weekly paclitaxel for advanced ovarian cancer. J Clin Oncol 32(15 Supplement), Abstract 5521Google Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Suzanne F. Jones
    • 1
    Email author
  • Lillian L. Siu
    • 2
  • Johanna C. Bendell
    • 1
  • James M. Cleary
    • 3
  • Albiruni R. A. Razak
    • 2
  • Jeffrey R. Infante
    • 1
  • Shuchi S. Pandya
    • 4
  • Philippe L. Bedard
    • 2
  • Kristen J. Pierce
    • 5
  • Brett Houk
    • 6
  • W. Gregory Roberts
    • 5
  • S. Martin Shreeve
    • 6
  • Geoffrey I. Shapiro
    • 7
  1. 1.Sarah Cannon Research InstituteNashvilleUSA
  2. 2.Princess Margaret Cancer CentreTorontoCanada
  3. 3.Brigham and Women’s HospitalBostonUSA
  4. 4.Beth Israel Deaconess Medical CenterBostonUSA
  5. 5.Pfizer OncologyGrotonUSA
  6. 6.Pfizer OncologyLa JollaUSA
  7. 7.Dana-Farber Cancer InstituteBostonUSA

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